Efficacy of non-conventional synthetic DMARDs for patients with rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis

Objectives We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). Methods PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant articles from inception to 1 June 2022. The results obtained from the analysis were expressed as mean difference (MD), effect size and 95% CI. Results A total of 17 studies, including 1315 patients with RA-ILD, were eligible. The ncs-DMARDs included abatacept, rituximab, tocilizumab, tumour necrosis factor and Janus kinase inhibitors. Compared with the baseline, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) values in the pooled data after ncs-DMARD treatment (alone or combined with conventional therapy) (p=0.36 for FVC; p=0.96 for FEV1 and p=0.46 for DLCO). Of note, FVC was obviously increased in rituximab subgroup (MD=−4.62, 95% CI −8.90 to −0.33, p=0.03). Also, high-resolution CT non-progression rate and fatality rate due to ILD progression in patients with RA-ILD were 0.792 (95% CI 0.746 to 0.834, p=0.015) and 0.049 (95% CI 0.035 to 0.065, p=0.000), respectively. Conclusion ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment for stabilising or improving ILD in patients with RA-ILD. PROSPERO registration number CRD42022356816.


INTRODUCTION
3][4] The severe ILD caused by RA negatively affects people's health worldwide. 5It has been reported that the death hazard rate in patients with RA-ILD is 2-10 times that of patients with RA without ILD, 6 making it the second leading cause of premature death in patients with RA after cardiovascular disease.At present, the exact pathogenesis of RA-ILD remains unclear.8][9] It is

WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ Interstitial lung disease (ILD) is the most common extra-articular manifestation of rheumatoid arthritis (RA).For the past of years, non-conventional synthetic disease-modifying antirheumatic drugs (ncs-DMARDs) have been widely used in patients with RA.However, therapeutic impacts of ncs-DMARDs on patients with RA-ILD were controversial in the previous literature.

WHAT THIS STUDY ADDS
⇒ In this study, almost all ncs-DMARDs used in RA were comprehensively analysed to explore their effects on the pulmonary changes of patients with RA-ILD.The pooled results showed that the pulmonary conditions of patients after ncs-DMARD treatment were stable, relatively.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
⇒ Our results indicated ncs-DMARD therapy favours stable or improved lung disease in patients with RA.
RMD Open RMD Open RMD Open also worth noting that apart from the natural course of RA and infection, disease-modifying antirheumatic drugs (DMARDs) may induce or worsen ILD. 10 In this situation, making the decision with patients in therapeutic regimens is more complicated.
Growing evidence highlights that ncs-DMARDs for RA have a good curative effect 12 13 ; however, their therapeutic impact on the progression and outcomes of ILD in patients with RA is controversial.Antoniou et al 14 found that patients with RA-ILD had significantly improved exercise tolerance and stabilised lung function after 1 year of therapy with infliximab.On the contrary, Lindsay et al 15 showed that a patient with RA-ILD presented with progressive dyspnoea and severe ground-glass changes in HRCT after 6 weeks of etanercept.Here, we conducted a systematic literature review and meta-analysis to evaluate the impact of ncs-DMARDs on the ILD outcomes in patients with RA to provide therapeutic decisions for ncs-DMARDs in patients with RA-ILD.

METHODS
The present study was registered on PROSPERO (CRD42022356816) and performed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. 16arch strategy PubMed, the Cochrane Library, EMBASE and Web of Science Databases were searched for relevant literature published from inception to 1 June 2022, using the following search terms: rheumatoid arthritis, interstitial lung disease and ncs-DMARDs approved for treatment of RA (online supplemental appendix 1).

Study selection
Two investigators (HY/SC) independently scanned the titles and abstracts of all retrieved articles to select matched studies.Any researcher disagreements were resolved through discussion, and a third person (LY) determined the final result.The inclusion criteria were as follows: (1) the study population included patients diagnosed with adult RA-ILD, without consideration of gender, race and pattern of ILD of patients; (2) the therapeutic regimen of patients included the application of ncs-DMARDs alone (at least one dose) or in combination with others; (3) clinical trials as well as cohort and case-control studies.Exclusion criteria were as follows: (1) non-English literature; (2) repeatedly published data; (3) literature with incomplete data or lacking target indicators; (4) review articles, letters, conference proceedings, editorials and case reports.

Data extraction and outcome measures
Two reviewers (HY/SC) independently extracted the following information by using a data extraction form: first author, published year, country, research type, sample size (female/male), mean age, duration of RA-ILD, follow-up time, pattern of ILD, other airway diseases, types of ncs-DMARDs, adverse events (AEs) and indicators.In the case of unavailability of detailed information, the data were obtained by contacting the original author through email.The Cochrane risk of bias assessment tool and Newcastle-Ottawa Scale (NOS) were used to evaluate the bias risk of randomised controlled trials (RCTs) and non-RCT studies. 17The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework classified with high, moderate, low or very low grade. 18The primary outcomes were forced vital capacity (FVC) and diffusion lung capacity for carbon monoxide (DLCO).The second outcomes were forced expiratory volume in the first second (FEV 1 ), non-progression rate of HRCT and fatality rate.The non-progression rate of HRCT was defined as the percentage of stable or improved images in patients with RA-ILD who underwent HRCT.The fatality rate was calculated as the percentage of patients with RA-ILD who died due to ILD progression.

Statistical analysis
The extracted data, including FVC, FEV 1 and DLCO, were analysed using Revman V.5.4 software (Cochrane Collaboration).Single-group results (eg, non-progression rate of HRCT and fatality rate) were pooled and analysed by using STATA V.16.0.For continuous outcomes, pooled outcomes were presented as a mean difference (MD) and 95% CI for analysis, while for single-group rates, effect size and 95% CI were used for analysis.The I 2 value was used to evaluate heterogeneity.Generally, we used the fixed-effects model to analyse substantial homogeneous trials (I 2 ≤50%, p>0.1).When statistical heterogeneity existed (I 2 >50%, p<0.1), we used a random-effects model followed by sensitivity analyses and subgroup analyses, which were carried out by gradually removing studies and performed according to types of drugs.STATA V.16.0 software and Egger's test were used to evaluate publication bias for studies involving FVC and DLCO.

Study selection
According to the above search strategy, 2601 articles were initially retrieved from five databases, and 2208 were acquired after the removal of duplicates.Next, the titles and abstracts of articles were screened for potential eligibility, and 33 were considered for full-text review, which

Quality evaluation of the included studies
A total of 17 articles were evaluated using the NOS, 17 3 of which were of moderate quality and 14 were of high quality, as shown in online supplemental table 1.The evidence quality of outcomes judged by GRADE 18 is depicted in online supplemental table 2. Concerning FVC and DLCO, evidence ranged from moderate to very low, and for HRCT non-progression and fatality rates, evidence ranged from moderate to low.We observed FEV 1 with moderate quality of evidence.
FVC and FEV 1 FVC, one of the crucial components of the pulmonary function test (PFT), is a significant indicator for detecting     2A).Additionally, four patients with RA-ILD who received baricitinib showed a nearly 10% increase in FEV 1 /FVC% after 6 months of follow-up in the research by d'Alessandro et al. 24 FEV 1 is closely related to FVC, which refers to the volume of exhaled air in the first second of maximum exhalation after maximum deep inspiration.As shown in figure 2B, FEV 1 changes in three studies, including 75 patients with RA-ILD, were compared before and after ncs-DMARD treatment.The analysis of the fixedeffects model proved that the FEV 1 remained unchanged in patients with RA-ILD who received ncs-DMARDs (I 2 =39%, p=0.20;MD=0.16, 95% CI −5.85 to 6.17, p=0.96; figure 2B).

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Diffusion lung capacity for carbon monoxide DLCO reflects the diffuse function of the lung.Here, a meta-analysis of nine studies with 313 patients with RA-ILD showed that the result of the pooled DLCO changes was not significant after ncs-DMARDs involving ABA, RTX, TCZ and JAKis (MD=−2.16,95% CI −5.41 to 1.10, p=0.19), as shown in figure 3A.A random-effects model was used for analysis because of the high heterogeneity (I 2 =54%, p=0.02; figure 3A).Furthermore, we performed sensitivity analysis by sequentially removing studies.As shown in figure 3B, after eliminating Narváez et al 22 in the RTX group with the wide 95% CI, there were no apparent changes in the left of merging results, indicating the outcomes were stable and reliable (MD=−0.81,95% CI −2.95 to 1.32, p=0.46; figure 3B).The results of subgroup analysis according to the different ncs-DMARDs showed no apparent changes in DLCO in patients with RA-ILD treated with ABA or RTX (I 2 =0%, MD=−0.65,95% CI −3.58 to 2.28, p=0.66 for ABA; I 2 =0%, MD=0.01, 95% CI −4.16 to 4.17, p=1.00 for RTX; figure 3B).Our results revealed stable lung diffuse function in patients with RA-ILD after ABA or RTX treatment.

Non-progression rate of HRCT
In our meta-analysis, all the HRCT images of patients with RA-ILD were assessed at the baseline and the end of the follow-up time ( was done by an experienced radiologist with a blind approach and identified by another senior radiologist if there were suspicious cases.Our results demonstrated that the HRCT non-progression rate in patients with RA-ILD treated with ncs-DMARDs (ABA, RTX, TCZ, JAKis) was 0.792 (95% CI 0.746 to 0.834, p=0.000 by STATA V.16.0 software; figure 4) in 399 patients from 10 studies, which means the pulmonary radiographical images of majority of the patients with RA-ILD were steady or improved.Next, we used a homogeneous fixedeffects model to analyse the subgroup data based on ncs-DMARD types (I 2 =12.399%; figure 4), finding that the non-progression rate of HRCT in patients treated with ABA was 0.804 (95% CI 0.747 to 0.856, p=0.000), and the rate of RTX was 0.661 (95% CI 0.542 to 0.773, p=0.000; 80.4% vs 66.1%; figure 4).

DISCUSSION
After repeated screening and checking, 17 self-controlled studies encompassing 1315 patients with RA-ILD were included.Despite different types of ncs-DMARDs, our data showed that ncs-DMARD therapeutic regimen might effectively stabilise PFT or HRCT and decrease the fatality rate of patients with RA-ILD owing to progressive ILD.
To explore the impact of ncs-DMARDs on ILD in patients with RA, we also focused on indicators including FVC, FEV 1 , DLCO and HRCT changes.Our results showed that the overall FVC data indicated the stable pulmonary situation of patients after treatment, achieving higher statistical significance after 6-70 months of follow-up in the RTX group, suggesting improving lung function in patients with RA-ILD.In particular, Fernandez-Diaz et al showed that FVC of patients with RA-ILD with ABA treatment steadily rose (86.2% to 87.6%) after 12 months of follow-up, which was followed by a slightly downward trend (86.2% to 85.1%) at the end of 22 months. 20This was probably due to the progression of the primary disease, which suggests that more aggressive therapeutic drugs should be considered.Regarding FEV 1 , our results detected no statistical significance in patients with RA-ILD while indicating that ncs-DMARD therapy could stabilise patients' lung function.Unsurprisingly, the FEV 1 , which is closely related to FVC, was not significantly improved in the RTX group because of insufficient data.
In addition, regardless of whether Narváez et al's study was excluded from the sensitivity analysis or not, 22 DLCO of patients with RA-ILD treated with ABA and RTX was relatively stable, suggesting that patients did not have an apparent deterioration of lung diffuse function.Meanwhile, Tardella et al 27 showed that JAKis combined with steroids might slightly improve the DLCO of the patients (59.7% to 62.8%).Consistent with the above observations, in some case reports, JAKis regimen improved DLCO without pulmonary deterioration or infection in patients with RA-ILD after 8-12 months of follow-up. 36 37s shown in figure 4, 11 of 19 studies calculated the non-progression rate of HRCT after treatment with ncs-DMARDs.Additionally, the HRCT pattern of ILD made a difference in the prognosis of RA.One identified UIP as the predominant pattern 38 ; however, in our population, the percentages of patients with a UIP pattern versus an NSIP pattern were similar (18% vs 15%, respectively).Nonetheless, with 782 patients with unknown patterns, it is challenging to truly know the predominant radiological pattern of ILD in our pooled population.Of the five studies in this report, 22 23 31 32 35 radiographical worsening data were recorded in 15 of the 38 patients with UIP patterns.In contrast, only 9 of the 53 patients with NSIP pattern had deterioration of HRCT, indicating the NSIP type may better respond to ncs-DMARDs.Of note, HRCT after RTX treatment was not routinely performed in all patients (if stable), which might decrease the real non-progression rate in the RTX group.
It was reported that the median survival of patients with RA after diagnosis of ILD was 2.6-8.5 years in different US cohort studies, which was significantly shorter than the expected years of patients with RA of the same age and sex, about 16% of whom died from ILD deterioration. 39 40For the death of patients with RA-ILD treated

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with DMARDs, our meta-analysis revealed that with 3.8-year follow-up, the rate due to ILD deterioration (ILD as the main cause of death) was 6.4% and 16.5%, respectively in TNFis and RTX subgroup.Notably, the pulmonary comorbidities (such as chronic obstructive pulmonary disease or asthma) in patients from the

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RTX group were more severe (41.9%). 30On the contrary, Kelly et al found that RTX therapy was more effective than our results suggested (4% vs 16.5%), although it was based on respiratory mortality, including that caused by infection or pulmonary embolism. 41These differences were explained by inconsistency in the evaluation criteria of death cause, ILD severity, HRCT patterns and pulmonary comorbidities, all of which might contribute to the relatively high case fatality rate in the RTX group observed in the present study.At the same time, the other differences in sample sizes should not be ignored.In our data, the other AEs including infections (respiratory, n=62; others, n=14), 20-23 25 28 32 hospitalisation owing to non-infections (n=48), 32 local infusion reaction (n=1) 20 and hypogammaglobulinaemia (n=10) 22 25 were reported during ncs-DMARD treatment.However, there was no exact link between infection and the combined use of ncs-DMARD strategies.
As far as drug details are concerned, RTX and TNFis were entirely applied with either cs-DMARDs (MTX, AZA, MMF, LEF, TAC, SSZ, HCQ) or glucocorticoids, while ABA, TCZ and JAKis were recorded as monotherapy or combined regimen.The overall risk of lung exacerbation attributed to MTX is controversial.Some research reported that MTX treatment led to RA-ILD progression in patients with RA. 27 42 Nevertheless, in our literature, the majority of studies indicated that MTX did not cause the progression of ILD. 23 28 34Similarly, growing studies suggested that MTX in monotherapy or combined with bDMARDs was not associated with an increased risk of RA-ILD in patients, actually it might be equally effective and safe. 2 43 44 Importantly, the 2021 ACR guidelines for RA treatment conditionally favour MTX for patients with mild and stable airway or parenchymal lung disease, because of the anchor status as a DMARD and lack of alternatives with efficacy and long-term safety. 45As glucocorticoids with stable low doses (eg, prednisolone and methylprednisolone) were found to be used in most patients with RA throughout the follow-up, we confirmed that steroid use had no impact on ILD outcomes in our data.It is worth mentioning that antifibrotic drugs (eg, nintedanib and pirfenidone) were not applied in the patients enrolled in our research, providing little therapeutic influence on our final results.
Undoubtedly, increased evidence indicates rheumatoid factor (RF) and/or anti-cyclic citrullinated protein (CCP) seropositivity has been the risk factors for ILD susceptibility. 46 47Of the 11 studies in our data, the RF and anti-CCP seropositivity were recorded in 727 of 891 (81%) and 295 of 339 (87%) patients, respectively. 20-23 26-29 32 33 35egarding the relationship between the RF or anti-CCP seropositivity and the effect of the biological treatments on the progression of ILD, four of our included studies indicated that the RF seropositivity was irrelevant to RA-ILD deterioration after ncs-DMARD treatment (ABA, JAKi, TNFi) 23 27 28 34 ; inversely, Detorakis et al found that serum levels of anti-CCP considerably decreased in the RA-ILD group following TNFi treatment. 28More studies with stratified seropositive or seronegative group are needed to provide detailed information.
Nevertheless, the present study has some limitations.First, the included literature was mainly self-controlled studies, where the natural course of the disease might interfere with clinical outcomes.Simultaneously, we should consider the impact of combining regimens on disease progression.Future well-designed RCTs with different ncs-DMARD therapy groups (monotherapy, combination and cs-DMARDs alone) on RA-ILD are needed to further confirm reported findings.Second, the outcomes of certain ncs-DMARDs such as TCZ and JAKis were insufficient due to few eligible studies, and data from relevant clinical trials with large sample sizes are essential.Finally, due to confounding factors, it is necessary to conduct stratified analysis, for example, comorbidities, radiographical patterns and the severity of ILD.A new concept, progressive pulmonary fibrosis (PPF), was proposed in 2022.It was defined by meeting at least two of three criteria (worsening symptoms, radiological progression and physiological progression) occurring in the past year without an alternative explanation other than idiopathic pulmonary fibrosis in patients with ILD. 48Hence, it is critical to recognise early PPF state in patients with RA-ILD and timely adjust treatment regimen in order to improve patients' prognosis.

CONCLUSION
Our data suggest that ncs-DMARD therapy might stabilise FVC, FEV 1 and DLCO values in the pooled data.Of note, there was a significant improvement in FVC changes in the RTX subgroup.In addition, patients' HRCT nonprogression and fatality rates after ncs-DMARD treatment were 79.2% and 4.9%, respectively.Generally speaking, ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment that could stabilise lung function and arrest the progression of ILD in patients with RA-ILD.
the inclusion criteria.Finally, 17 studies, including 16 quantitative studies, were identified.All the included patients met the 1987 American College of Rheumatology (ACR) or the 2010 ACR/European Alliance of Associations for Rheumatology classification criteria of RA.Details of the study screening are shown in figure 1.

Figure 1
Figure 1 Flow chart of included studies and excluded reasons.

Figure 2 (Figure 3
Figure 2 (A) Meta-analysis of self-control studies to assess FVC changes in patients with RA-ILD treated with different types of ncs-DMARDs; (B) meta-analysis of self-control studies to assess FEV 1 changes in patients with RA-ILD treated with different types of ncs-DMARDs.ABA, abatacept; FEV 1 , forced expiratory volume in the first second; FVC, forced vital capacity; ILD, interstitial lung disease; JAKis, Janus kinase inhibitors; ncs-DMARDs, non-conventional synthetic disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; RTX, rituximab; TCZ, tocilizumab; TNFis, tumour necrosis factor inhibitors.

Figure 5
Figure 5 Meta-analysis of self-control studies to assess the single-group case fatality rate of patients due to ILD progression in patients with RA-ILD treated with ncs-DMARDs.ABA, abatacept; ES, effect size; ILD, interstitial lung disease; ncs-DMARDs, non-conventional synthetic disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; RTX, rituximab; TNFis, tumour necrosis factor inhibitors.

Figure 6
Figure 6 Egger's test to assess the publication bias of primary outcome.MSE, mean squared error; DLCO, diffusion lung capacity for carbon monoxide; FVC, forced vital capacity.

Table 1
Basic characteristics of the included studies the respiratory tract.In the current study, some patients with RA-ILD presented with abnormalities in FVC.Meta-analysis of 12 studies, including 465 patients with RA-ILD, showed that FVC did not significantly change after being treated with ncs-DMARDs, including ABA, RTX, TNFis, TCZ and JAKis (MD=−0.93,95%CI−2.91 to 1.05, p=0.36), as shown in figure2A.A fixed-effects model was used for low heterogeneity for either the pooled or